Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors

Authors:
  • YLYongfu Liu
    Yongfu Liu
  • JWJun Wu
    Jun Wu
  • MZMingwei Zhou
    Mingwei Zhou
  • WCWenming Chen
    Wenming Chen
  • DLDongbo Li
    Dongbo Li
  • ZWZhanguo Wang
    Zhanguo Wang
  • BHBenoit Hornsperger
    Benoit Hornsperger
  • JAJohannes D. Aebi
    Johannes D. Aebi
  • HMHans-Peter Märki
    Hans-Peter Märki
  • LWLisha Wang
    Lisha Wang
  • AKAndreas Kuglstatter
    Andreas Kuglstatter
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Abstract
Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure–activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 52, in an in vivo cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.
Funding Information
  • F. Hoffmann-La Roche

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